|Year : 2015 | Volume
| Issue : 3 | Page : 95-102
Clinical profile and prognostic markers of acute febrile encephalopathy (AFE) in adult patients presenting to a North Indian tertiary care hospital
Ruhi Khan, Saif Quaiser, Sarah Alam
Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
|Date of Submission||10-Mar-2015|
|Date of Acceptance||25-Mar-2015|
|Date of Web Publication||8-Jun-2015|
Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh - 202 002, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Acute febrile encephalopathy (AFE) is a clinical term used to an altered mental state that either accompanies or follows a short febrile illness and is characterized by a diffuse and nonspecific brain insult manifested by a combination of coma, seizures, and decerebration. Objective: To identify the clinical and etiological profile of acute febrile encephalopathy in adult patients presenting to JNMCH, Aligarh from January-December, 2014. Patients and Methods: 238 adults (>14 yrs.) presenting to the emergency with complains of fever (>38C) of less than 2 weeks duration with altered sensorium with/or without seizure were prospectively investigated for etiological cause. The investigations included routine blood investigations, chest X-rays, cerebrospinal fluid (CSF) microscopy, bacterial and fungal cultures, CSF serology, peripheral smear and serology for malarial parasite. Other investigations included were CT or MRI wherever indicated. Non-infectious causes were ruled out by various investigations mentioned above. Outcome was evaluated by the report of investigations and response to treatment over during the period of inpatient treatment. Results: Out of all the patients admitted, acute pyogenic meningitis was the most common cause accounting for 34.5% of cases followed by cerebral malaria 20.2%, sepsis associated encephalopathy 14.3%, acute meningoencephalitis 9.2%, tubercular meningitis 6.7%, enteric encephalopathy 2.5% and fungal meningitis in 1.3% cases. Conclusion: Acute pyogenic meningitis is the most common cause of AFE in the patients who reported to JNMCH in the past one year. Prompt and specific treatment can mimimise morbidity and mortality in many cases presenting with AFE.
Keywords: Dengue, encephalopathy, malaria, meningitis, sepsis
|How to cite this article:|
Khan R, Quaiser S, Alam S. Clinical profile and prognostic markers of acute febrile encephalopathy (AFE) in adult patients presenting to a North Indian tertiary care hospital. Int J Nutr Pharmacol Neurol Dis 2015;5:95-102
|How to cite this URL:|
Khan R, Quaiser S, Alam S. Clinical profile and prognostic markers of acute febrile encephalopathy (AFE) in adult patients presenting to a North Indian tertiary care hospital. Int J Nutr Pharmacol Neurol Dis [serial online] 2015 [cited 2019 Oct 13];5:95-102. Available from: http://www.ijnpnd.com/text.asp?2015/5/3/95/158320
| Introduction|| |
Acute febrile encephalopathy (AFE) is a clinical syndrome assigned to patients presenting with complains of altered mental state associated with short febrile illness. It is one of the most common causes of emergency and outdoor admissions in a hospital setting. Besides infectious etiologies, which are the most common cause of non-traumatic comas,  encephalopathy can be attributed to other systemic complications like hyperpyrexia, electrolyte imbalance, hypoxia, or hypoglycemia. The profile of such patients is also subject to demographic and seasonal variations even in the same area. Our country being endemic for age-old conventional pathogens like plasmodium, Salmonella More Details, and mycobacterium we are now also up against the threat of new viruses causing AFE in our region.  The clinician has to be vigilant enough to identify the underlying etiology in most of the cases and treat accordingly as most patients with AFE like cerebral malaria and enteric encephalopathy can make full recovery. 
This study was carried out to evaluate the etiological, clinical profile, and prognostic markers associated with outcome in adult patients (>14 years) admitted in medicine wards of Jawarharlal Nehru Medical College, Aligarh with a diagnosis of AFE over a one-year period.
| Patients and methods|| |
All patients above 14 years of age admitted between January and December 2014 with fever of less than 2 weeks duration with altered mentation, either at onset or following fever, and lasting at least 24 h were enrolled into the study. Exclusion criteria included patients in whom persistent altered mental state could be attributed to one or more deranged metabolic parameters such as hypoglycemia (<50 mg/dL), hypoxia (PaO2 <60 mm Hg), hypercarbia (PaCO2 >50 mm Hg), hyponatremia (<120 mg/dL), hypernatremia (>150 mg/dL), azotemia (serum creatinine >2.5 mg/dL), space-occupying lesion (ICSOL), or endocrinopathies. Patients having cerebrovascular diseases followed by fever were also excluded as structural lesion in the brain could be a reason for the altered mental state. Moreover, patients with any previous psychiatric illness or any related drug treatment were also excluded.
History and clinical examination was done in all the patients with fever with altered mental state of short duration. Investigations included: Complete hemogram, metabolic profile, chest radiography, and electrocardiogram. A Histidine-rich, protein-based immunochromatographic card test for Plasmodium falciparum malaria, quantitative buffy coat test for Plasmodium vivax malaria, and peripheral smear for malarial parasite, dengue serology, and leptospira antibody was examined in all the patients. Samples for blood cultures and urine cultures were collected and any clinically obvious site of sepsis was investigated. Lumbar puncture was carried out in all the patients at admission and cerebrospinal fluid (CSF) was analyzed for cytology, protein levels, glucose-to-blood glucose ratio, gram stain, culture sensitivity for microbes, malignant cells, adenosine deaminase levels, dengue serology and India ink staining, where required. All patients underwent a contrast-enhanced computed tomography (CT) of the brain. This was followed by a magnetic resonance imaging (MRI) scan of the brain using contrast, if required. Serological tests for the herpes simplex virus (HSV), dengue, hepatitis A, B, E, and the human immunodeficiency virus (HIV) were done as investigations for other viral etiologies were not available in our institute at the time of this study. The patients were classified into broad groups of meningitis, meningoencephalitis, and other clinical syndromes on the basis of pre-designated diagnostic criteria as seen in [Table 1].
The results were analyzed using SPSS statistical software version 19. The values were expressed as mean with standard deviation (S.D.) for contiguous variable as percentage for the others. P value of <0.5 was taken as statistically significant.
| Results|| |
During the study period, a diagnosis of AFE was established in a total of 238 patients after applying the exclusion criteria. The age of patients ranged from 15 to 73 years, with a mean of 33.89 17.31 years. There were 149 (62.6%) males and 89 (37.4%) females. The most common complaints were fever (100%), headache (94%), and an altered mental state (100%). Seventy-six (32%) of the patients had seizures at presentation. Neck stiffness was present in 86 (36%) patients. The Glasgow Coma Scale (GCS) score at the time of presentation was ≤7 in 46 (19.32%) patients, while 192 (80.7%) patients had a GCS of >7, as shown in [Table 2].
|Table 2: Characteristics of patients with acute febrile encephalopathy (AFE) with different etiologies |
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Of the 238 patients, pyogenic meningitis (PM) 82 (34.5%) was the most common etiology, followed by CM (CM) in 48 (20.2%) patients. A total of 98 (41.2%) patients had meningitis, with 82 (34.5%) patients having acute PM and 16 (6.7%) patients having tubercular meningitis (TBM). Forty-eight patients (20.2%) had evidence of CM, which was followed by acute meningoencephalitis (AME) in 22 (9.2%) cases as a cause of primary central nervous system (CNS) infection. Thirty-four patients (14.3%) had infections elsewhere and were diagnosed as sepsis-associated encephalopathy (SAE). Six patients (2.5%) were diagnosed as having enteric encephalopathy, 3 (1.3%) as fungal meningitis-candida albicans (two focal segmental glomerulosclerosis patients on oral steroids and one chronic myeloid leukemia patient receiving imatinib) and one (0.4%) each as cortical venous sinus thrombosis (CVT) due to mastoiditis and heat stroke. In 25 patients (10.5%), the final diagnosis could not be made in spite of the extensive investigations available in our center.
Twenty-two (9.2%) patients of acute AME included 4 patients with HSV encephalitis, 2 patients with dengue, and 1 patient with acute viral hepatitis A encephalitis. In the remaining 15 patients, the etiology was not identified, as seen in [Figure 1] and [Table 3].
|Figure 1: Evaluation of adult patients with acute febrile encephalopathy|
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Among patients of AME, the definite diagnosis of HSV encephalitis in 4 (1.7%) patients was based on MRI and CSF serology reports. In the remaining 15 patients, definite diagnosis could not be made despite doing all possible investigations available in our institute and presumptive diagnosis of AME was considered on the basis of clinical features and routine CSF studies. Among the cases of PM, CSF culture was positive in only 14 patients out of which streptococcus pneumoniae was identified in 9 cases and staphylococcus aureus in 5 cases. The reason for negative CSF culture may be that the cases were referred from primary or secondary care centers, at which they might have been given antibiotics.
The majority of patients (139/238) were seen during the period between June and September. This is the period of the year when the temperatures rise due to heat (May-July), followed by rains and post-monsoon period (June-September). Seasonal variation of prevalence in cases of AME and CM was observed in our study too as shown in [Figure 2].
|Figure 2: Seasonal variation of prevalence in cases of AFE |
PM = Pyogenic meningiti, AME = Acute meningoencephalitis, TBM = Tubercular meningitis, CM = Cerebral malaria
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CT scans of the brain as baseline imaging were done in all the AFE patients. Only 48 patients had shown abnormalities on imaging, CT, or MRI. Meningeal enhancement was seen in 43% patients with PM. MRI brain scan was performed in only 12 patients with AME. The bilateral T2 thalamic hyperintensities, in particular hemorrhages, was the most common finding seen in 5 patients out of 12 patients in whom MRI brain scans were done. MRI brain scabs in two patients out of four patients of HSV encephalitis showed characteristic T2-weighted hyperintensity corresponding to edematous changes in the temporal lobes. In 7 patients, nonspecific MRI findings of meningeal enhancement with cerebritis and cerebral infarction were seen.
In this study, 29 patients died during the hospital stay, 7 with SAE, 5 due to AME, 3 due to PM, 2 due to CM, and 12 in whom no diagnosis could be made.
The prognostic factors associated were poor prognosis were age >60 years; shock at presentation, duration of illness at presentation >7 days; GCS <7 at presentation; focal neurological deficit (FND) at presentation; etiological diagnosis of SAE, AME, or no diagnosis; and CT/MRI findings suggestive of thalamic lesions as shown in [Table 4].
| Discussion|| |
Fever with altered mentation is one of the most common presenting symptom leading to hospital admissions in both adults and children in our country and is also known as AFE. Fever with altered mental status is commonly caused by bacterial meningitis, Japanese B encephalitis (JE), CM, typhoid encephalopathy, and fulminant hepatic failure due to viral hepatitis.  Various studies in children with nontraumatic coma have shown that CNS infections are the commonest cause of nontraumatic coma.  However, very few studies  have been conducted in adults in our country, none in our geophraphical or demographic profile. In the present study, we have tried to evaluate the common etiologies of acute febrile encephalopathy encountered in adults in a tertiary care center in Western Uttar Pradesh.
A study of non-traumatic coma in children has indicated that TBM, PM, and encephalitis together constitute more than 90% of the cases.  In another study of 151 children, viral encephalitis was the most common etiology seen in 57 patients. A diagnosis other than viral encephalitis was reached in 94 patients (62.3%). PM was the most frequent diagnosis (33.8%), followed by TBM (7.9%), and CM (5.2%) in the patient group of non-viral causes.  Our findings in adults are a bit different from this study. Eighty four percent of our patients had primary CNS infections as the major cause of altered mentation in febrile patient with 41.2% of our patients having meningitis. This was followed by SAE as the second-most common cause as shown in [Table 5]. Primary meningeal infection became the predominant cause of acute febrile encephalopathy in our study group. CM was the second major group among the primary CNS infections. The reason for the lower prevalence of TBM as an etiology for AFE in adults as compared with children could be the sub-acute/chronic presentation of TBM in adults.
In as many as 25 (10.5%) of the 238 cases, even after all the investigations (serology, CSF, CT, and MRI), we could not arrive at a definite diagnosis. This figure is much lower than that reported in the literature. ,
We noted a male predominance in our study with males constituting around 62.6% of the study population and a 2:1 male-to-female ratio in patients with meningoencephalitis and a very similar male predominance was noted in a study in HSV encephalitis by Panagaria et al.  None of the CNS infections are known to have a male predominance, yet this apparent male predominance can be attributed to the male-dominated social system where a sick male gets preferential medical attention. Moreover males in our society indulge in outdoor activities more often due to work making them more susceptible to vector-borne infectious diseases.
It is postulated that alteration in sensorium in a patient with CNS infection indicates an element of parenchymal involvement. , This can explain the altered mentation in meningoencephalitis patients. In CM, primary parenchymal involvement may be responsible for encephalopathy, but altered mentation in primary meningeal involvement is difficult to explain. Raised intracranial pressure may contribute to altered mentation to some extent. The reason for altered sensorium in meningitis is postulated to be the spillage of inflammatory cells to the adjacent brain parenchyma and the resultant parenchymal involvement.  In SAE, metabolic alterations and inflammatory cytokines may play an important role in the pathogenesis of encephalopathy rather than direct parenchymal involvement. Encephalopathy in CVT may be a direct result of the parenchymal involvement, but the fever may be due to the predisposing condition.
HSV is a common cause of sporadic encephalitis around the world.  Post-monsoon JE has been reported from many parts of India. The less common varicella encephalitis tends to be fatal in immunocompromised patients. Among the other identifiable viruses, enterovirus, JE virus, and mumps are important agents.  In our study, the most commonly identifiable cause of encephalitis was herpes simplex encephalitis followed by hepatitis and dengue. The complete virologic screen was not available to us and hence, we could not identify the culprit virus in a substantial number of our patients.
CM, the potentially fatal complication of P. falciparum malaria is an important cause of unarousable coma in febrile patients in endemic areas. In the endemic areas, CM remains an important differential in patients presenting with acute fever and altered sensorium.  The post-monsoon surge in malaria cases coincides with that of viral encephalitis and the common symptomatology may be confusing to the physicians. Since Western Uttar Pradesh is endemic for P. falciparum malaria, we encountered a large number of CM cases in our study group.
Though dengue was earlier thought to be a non-neurotropic virus,  nowadays dengue encephalopathy is a well-recognized and common entity, the incidence ranging from 0.5 to 6.2%.  The possible mechanisms are liver failure (hepatic encephalopathy), cerebral hypoperfusion (shock), cerebral edema (vascular leak), deranged electrolytes, and intracranial bleeding due to thrombocytopenia or coagulopathy, which is secondary to hepatic failure.  There are subsets of patients in whom the cause for neurological injury remains unclear, even after excluding the above-mentioned indirect mechanisms. Dengue neurotropism has been suggested as the possible mechanism in such cases because of evidence of dengue virus  and dengue IgM antibodies  has been discovered in CSF of encephalopathy patients, which suggests that the dengue virus is capable of CNS infection.
In patients with dengue encephalopathy, MRI brain scan abnormalities are comprised of edema and scattered focal lesions, hemorrhage, and cerebral edema.  In our patients, there was also the presence of cerebral edema without any evidence of hemorrhage on the MRI.
Acute liver failure (ALF) is defined by the onset of jaundice, coagulopathy, and encephalopathy within 8 weeks, in the absence of prior liver disease.  There are several causes of ALF: metabolic diseases, vascular abnormalities, drug-induced (acetaminophen, Amanita) and viral hepatitis, which account for the majority of pediatric ALF cases in many areas of the world. Viral hepatitis A is one of the most important causes of ALF in children, besides hepatitis B, D, and E; the Epstein-Barr virus; and acetaminophen overdoses. Even though children are the main victims of hepatitis A in endemic areas, ALF is an infrequent complication among children, since the possibility of fulminant evolution rises with age, peaking above the age of 40 years.  Even though there is evidence of specific genetic features in viruses found in ALF patients,  the reason why some hepatitis A patients present ALF, whereas most of them present a self-limited picture, remains unknown. In ALF, massive hepatocellular necrosis takes place which accounts for jaundice, coagulopathy, and encephalopathy. The majority of processes eliciting ALF are transient, which means only supportive treatment is needed if the patient is able to survive long enough for the liver to recover its function.
SAE is a poorly-understood CNS condition that is associated with a wide range of manifestations from lethargy to overt delirium in sepsis patients. SAE has serious prognostic implications and it is an important predictor of higher 6 months mortality.  Since a large number of patients present to the emergency room in a tertiary care hospital with sepsis, it becomes an important differential diagnosis of acute febrile encephalopathy in adults. In our study population, we did encounter SAE as an important cause of AFE in adults.
Candidal meningitis is a rare and serious disease that may result in significant morbidity and mortality if not recognized and treated effectively.  In adults, it is seen most commonly in neurosurgical patients, immunocompromised patients, and patients with disseminated candidiasis  The most frequent symptoms are headache, photophobia, nuchal rigidity, and delirium, but an indolent course is also possible. The CSF usually shows a pleocytosis predominated by neutrophils and mononuclear cells, an elevated protein concentration, and a normal or low glucose concentration. The diagnosis relies mainly on the CSF culture, but laboratory values are not consistently helpful  In fact, there is substantial variability in CSF analysis. Several confounding factors complicate the establishment of a clinical diagnosis of candidal meningitis. First, it is difficult to isolate the Candida species from CSF because of the small inoculum size and slow growth. Second, isolated microorganisms must be ruled out as a source of contaminants. Third, the CSF cytological and biochemistry profile is too variable to allow a differential diagnosis. Despite the above diagnostic obstacles, there are several methods for improving the success of CSF isolation, such as: Ventricular CSF, and sediment of CSF centrifugation; use of a submicron filter; and inoculating CSF into enriched liquid medium, culturing a large volume of CSF (a minimum of 5 ml), , as done in our case.
A CT scan of the brain was performed as baseline imaging in all the patients with AFE firstly to rule out contraindications for lumbar puncture. Enhancement of the meninges was seen on contrast-enhanced CT scan in 35 (42.7%) cases of bacterial meningitis. However, meningeal enhancement is a nonspecific sign and may also be caused by other different etiologies like carcinomatous meningitis, reactive meningitis, and inflammatory vascular diseases of CNS. Imaging studies performed in patients with acute meningitis may provide normal findings. Our results also showed normal CT imaging in most of the patients of PM. Therefore, the results of an imaging study do not exclude or prove the presence of acute meningitis. MRI imaging of brain offers better resolution, it was performed when the findings of CT scan and CSF were inconclusive and patients were not fitting into the criteria of either CM or SAE. MRI brain scans in patients with HSV and JE may have characteristic findings.  MRI brain scans in patients with HSV encephalitis showed characteristic T2-weighted hyperintensities in the temporal lobes. Bilateral T2 thalamic hyperintensities, in particular hemorrhages, were the most common finding seen in patients with 6 out of the undiagnosed cases of AME in whom MRI brain was done. These findings are typical of JE, however in absence of serological assays/polymerase chain reaction (PCR), the diagnosis could not be confirmed. Two patients with TBM showed presence of hydrocephalus while ring enhancing lesion was seen in 1 patient of fungal meningitis.
A GCS and/or a focal neurological deficit at hospital admission were independent clinical markers of bad outcomes among children with AFE.  The lower frequency of bad outcomes among the AFE patients with bacterial or malaria infection is likely to reflect the availability and effective use of antibiotics and anti-malaria treatments to reduce morbidity among these patients.
Many acutely ill febrile patients with encephalopathy may make complete recoveries once the underlying cause is treated, but considerable skill is required to correctly diagnose the underlying etiology. The majority of our patients did make a complete recovery; however, a significant number of patients 29 (12.2%) died. The fact that maximum mortality was seen in patients with AME and SAE signifies that diffuse cerebral involvement, the unavailability of the specific drug for most of the viral infections, and multi-organ dysfunction in SAE might have contributed to a large extent in these patients. Raised intracranial pressure may have contributed to mortality in patients with meningoencephalitis. Mortality was also high in patients in whom a definitive diagnosis could not be made.
| Conclusion|| |
Our study is limited by the facts that firstly, PCR was not done for diagnosis of viral encephalitis and serology may not always be positive in the initial days. Secondly, the since complete serological screening for viral etiologies was not available in our center, we could not identify the culprit virus in a substantial number of our patients. Brain MRI scans were also not done in all patients due to poor affordability of the patients, which could have contributed in reaching the etiological diagnosis of AFE. To conclude, PM is the most common etiology identified, followed by CM and acute meningoencephalitis in patients with AFE. The outcome in cases with AME can be fatal or more disabling than other etiologies. Although dengue is not classically a neurotropic virus, Ddengue encephalitis must be thought of in differentials of encephalopathy, in patients with dengue. In such cases, neuroimaging and CSF analysis should be done whenever possible. Lastly fungal meningitis should always be kept in mind while managing an immunocompromised patient presenting with AFE not responding to conventional antibiotics.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]